Many naturally occurring, biologically active compounds are proteins or peptides based upon α-amino acids (i.e., sequences of α-amino acids in which the α-carboxyl group of one amino acid is joined by an amide bond to the α-amino group of the adjacent amino acid). In recent years an approach to the discovery of new pharmaceutically active drugs has been to synthesize libraries of peptides and then to assay for compounds within the library which have a desired activity, such as a desired binding activity. However, α-amino acid peptides are not altogether satisfactory for pharmaceutical uses, in particular because they are often poorly absorbed and subject to proteolytic degradation in vivo.
Much work on β-amino acids and peptides synthesized from β-amino acids has been reported in the scientific and patent literature. See, for example, the work performed by a group led by current co-inventor Samuel H. Gellman, including: “Application of Microwave Irradiation to the Synthesis of 14-helical Beta-Peptides,” Murray & Gellman,” Organic Letters (2005) 7(8), 1517-1520; “Synthesis of 2,2-Disubstituted Pyrrolidine-4-carboxylic Acid Derivatives and Their Incorporation into Beta-Peptide Oligomers,” Huck & Gellman, J. Org. Chem. (2005) 70(9), 3353-62; “Effects of Conformational Stability and Geometry of Guanidinium Display on Cell Entry by Beta-Peptides,” Potocky, Menon, & Gellman, Journal of the American Chemical Society (2005) 127(11):3686-7; “Residue requirements for helical folding in short alpha/beta-peptides: crystallographic characterization of the 11-helix in an optimized sequence,” Schmitt, Choi, Guzei, & Gellman, Journal of the American Chemical Society (2005), 127(38), 13130-1 and “Efficient synthesis of a beta-peptide combinatorial library with microwave irradiation,” Murray, Farooqi, Sadowsky, Scalf, Freund, Smith, Chen, & Gellman, Journal of the American Chemical Society (2005), 127(38), 13271-80. Another group, led by Dieter Seebach in Zurich, Switzerland, has also published extensively in the beta-polypeptide field. See, for example, Seebach et al. (1996) Helv. Chim. Acta. 79:913-941; and Seebach et al. (1996) Helv. Chim. Acta. 79:2043-2066. In the first of these two papers Seebach et al. describe the synthesis and characterization of a β-hexapeptide, namely (H-β-HVal-β-HAla-β-HLeu) 2-OH. Interestingly, this paper specifically notes that prior art reports on the structure of β-peptides have been contradictory and “partially controversial.” In the second paper, Seebach et al. explore the secondary structure of the above-noted β-hexapeptide and the effects of residue variation on the secondary structure.
Dado and Gellman (1994) J. Am. Chem. Soc. 116:1054-1062 describe intramolecular hydrogen bonding in derivatives of β-alanine and γ-amino butyric acid. This paper postulates that β-peptides will fold in manners similar to α-amino acid polymers if intramolecular hydrogen bonding between nearest neighbor amide groups on the polymer backbone is not favored.
Suhara et al. (1996) Tetrahedron Lett. 37(10):1575-1578 report a polysaccharide analog of a β-peptide in which D-glycocylamine derivatives are linked to each other via a C-1 β-carboxylate and a C-2 α-amino group. This class of compounds has been given the trivial name “carbopeptoids.”
Regarding methods to generate combinatorial libraries, several reviews are available. See, for instance, Ellman (1996) Acc. Chem. Res. 29:132-143 and Lam et al. (1997) Chem. Rev. 97:411-448.
In the recent patent literature relating to β-polypeptides, see, for example, U.S. published patent applications 2008/0166388, titled “Beta-Peptides with Antifungal Activity”; 2008/0058548, titled Concise Beta2-Amino Acid Synthesis via Organocatalytic Aminomethylation”; 2007/0154882, titled “Beta-polypeptides that inhibit cytomegalovirus infection”; 2007/0123709, titled “Beta-amino acids”; and 2007/0087404, titled “Poly-beta-peptides from functionalized beta-lactam monomers and antibacterial compositions containing same.” See also U.S. published patent application 2003/0212250, titled “Peptides.”